SUGAR-COATING HYPOALLERGENS ? A NOVEL APPROACH FOR SHELLFISH ALLERGY IMMUNOTHERAPY PROJECT SUMMARY/ ABSTRACT In the United States, shellfish is the third leading cause of food-induced anaphylaxis (16.1% of the 218 cases of food-induced allergy). Although shellfish avoidance and epinephrine administration are currently the first line of treatment in patients with anaphylactic responses to shellfish exposure, emerging strategies such as biomaterials-based allergen-specific immunotherapy hold tremendous promise for alleviating allergic responses. Biomaterial systems can precisely condition dendritic cells (DCs) in vivo. Dendritic cells represent a major group of professional APCs, which possess the capacity to polarize and re-program CD4+ T cells. In addition, it has been shown that tolerogenic DCs (tDCs) are, in turn, capable of inducing functional regulatory T cells and shift the immunological balance towards a non-allergic phenotype. For millennia, microorganisms have utilized immuno-modulatory biomaterials to co-exist in acerbic climates, including the mammalian gut. Taking our cue from nature, we to isolate and exploit the unique tolerogenic properties of polysaccharide A ? a molecule found in the cell wall of gut-residing bacteria that control DC polarity and ensuing immunological reactions to these commensal bacteria. Moreover, we believe that that encapsulation of hypoallergens by PSA microparticles (MPs) will reduce the allergenicity. The long-term goal of this program is to develop a modular, anti-allergy system for food allergy therapy. The overall objective of this R03 proposal is to engineer a PSA-based microparticle system, encapsulating hypoallergens, and ascertain it capacity to mitigate allergen-specific reactions in hypersensitized mice. The central hypothesis is that is that the rational design a dendritic-cell targeting, bacteria-derived, polysaccharide microparticle system will drive tolerization of shellfish hypoallergens (MEM49 and MED171) via induced IL-10?producing regulatory T cells, and, thereby promote attenuation of shellfish allergy. This hypothesis will be tested by pursuing three specific aims: 1) Build a PSA-based microparticle system that incorporates shellfish hypoallergens; 2) Investigate DC and T cell responses to PSA MPs in vitro; and 3) Evaluate the therapeutic efficacy of PSA MPs in a mouse model of antigen-driven, shellfish allergy. This approach is innovative because it departs from the status quo by generating specific tolerance-inducing cellular mediators in vivo with simple administration of hypoallergen-loaded, PSA-based MPs. Moreover, it incorporates both novel immunomodulatory biomaterials and engineered allergens to generate a system that is efficacious, safe and clinically translatable. Ultimately, the research and development of this system has the potential to significantly stem the growing epidemic of food allergy in the US.